Codeine is widely used as both an analgesic and antitussive drug. Codeine occurs naturally in opium to the extent of 0.3% to 4% depending on the source. Codeine is the methyl ether derivative of morphine, another naturally occurring opiate alkaloid. Morphine is present in opium in the range of 9% to 17% by weight. Although morphine is more abundant and a more potent analgesic drug than codeine, the market demand for codeine far exceeds that for morphine.
Codeine is generally prepared by methylating morphine. A trimethylanilinium salt is generally used as the methylating reagent with the counter anion being ethoxide, chloride or hydroxide. The reaction is generally run in toluene or xylene, and when the counter anion is chloride the reaction must be run in the presence of an organic base, such as sodium ethoxide, to remove the proton from the phenoxy group of morphine. Morphine is usually first dissolved in absolute ethanol and then added to the solution of the methylating reagent in a hydrocarbon solvent. Ethanol is distilled out during the reaction.
The prior art processes require the separation of codeine from the side product of the reaction, N,N-dimethylaniline, which is highly toxic and has been reported to be carcinogenic. This methylating reagent is generally not recycled or reused which increases the cost of the procedure and results in environmental concerns. In addition, both morphine and the organic solvents must be anhydrous which further increases the cost of the process. Both the reaction temperature and the ratio of the reactants also have to be strictly controlled in order to produce high quality codeine in good yield. The prior art processes also consume relatively large amounts of various solvents which are difficult to recycle. Finally, the prior art processes require, at the end of the reaction, that any unreacted morphine be removed from the codeine product.